16-2109556-C-T

Position:

chr16-2109556-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.5611G>A(p.Ala1871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,611,596 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0067 ( 54 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0155184865).

BP6

Variant 16-2109556-C-T is Benign according to our data. Variant chr16-2109556-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109556-C-T is described in Lovd as [Benign]. Variant chr16-2109556-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00434 (661/152352) while in subpopulation NFE AF= 0.00731 (497/68024). AF 95% confidence interval is 0.00678. There are 1 homozygotes in gnomad4. There are 291 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 661 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.5611G>A	p.Ala1871Thr	missense_variant	15/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.5611G>A	p.Ala1871Thr	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

661

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00731

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00425

AC:

1044

AN:

245780

Hom.:

AF XY:

0.00449

AC XY:

602

AN XY:

133936

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00549

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00659

Gnomad OTH exome

AF:

0.00466

GnomAD4 exome

AF:

0.00671

AC:

9789

AN:

1459244

Hom.:

Cov.:

AF XY:

0.00663

AC XY:

4810

AN XY:

725874

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.00249

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00598

Gnomad4 FIN exome

AF:

0.00161

Gnomad4 NFE exome

AF:

0.00782

Gnomad4 OTH exome

AF:

0.00561

GnomAD4 genome

AF:

0.00434

AC:

661

AN:

152352

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00731

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00438

Hom.:

Bravo

AF:

0.00479

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00572

AC:

ExAC

AF:

0.00411

AC:

495

EpiCase

AF:

0.00780

EpiControl

AF:

0.00719

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	This variant is associated with the following publications: (PMID: 17582161, 22608885, 30647506) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PKD1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 25, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ala1871Thr variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD, being classified as a polymorphism/likely neutral (Rossetti 2007, Rossetti 2012, Tan 2009, Tan 2014). The variant was identified in dbSNP (ID: rs144137200) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, Clinvitae and ClinVar (classification likely benign, submitter Prevention Genetics), and the ADPKD Mutation Database (classification likely neutral); but was not identified in GeneInsight-COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was also identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), HAPMAP-EUR in 3 of 1006 chromosomes (frequency: 0.003)/-AMR in 3 of 694 chromosomes (frequency: 0.0043)/-SAS in 2 of 978 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 49 of 8560 European American alleles (freq. 0.006) and in 6 of 4374 African American alleles (freq. 0.001), the genome Aggregation Database (beta, October 19th 2016) in 1142 (4 homozygous) of 272522 chromosomes (freq. 0.004) and in the Exome Aggregation Consortium database (August 8th 2016) 485 (4 homozygous) of 104730 chromosomes (freq. 0.0046) in the following populations: European (Non-Finnish) in 364 of 57774 chromosomes (freq. 006), South Asian in 84 of 15042 chromosomes (freq. 006), Other in 4 of 732 chromosomes (freq. 006), Latino in 20 of 10302 chromosomes (freq. 002), African in 10 of 8320 chromosomes (freq. 001), and in European (Finnish) in 3 of 4634 chromosomes (freq. 0006); but was not seen in East Asian; increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala1871 residue is not conserved in mammals and 4 out of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

0.027

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.82

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.28

T;T

Sift4G

Benign

0.20

T;T

Polyphen

1.0

D;D

Vest4

0.22

MVP

0.92

ClinPred

0.015

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over